loss of function is associated with the Von Hippel-Lindau disease
Product of the VHL gene is the protein pVHL.
Function of pVHL is ubiquitylation of HIF-1α, which is one of two subunits of the HIF-1(hypoxia-inducible factor-1) transcription factor.
Polyubiquitylation of HIF-1α leads to its degradation and therefore prevents the formation of a functional HIF-1.
A functional HIF-1 transcription factor causes expression of genes such as VEGF, PDGF, TGF-α, which are growth promoting genes in the context of establishing new blood vessels.
Normally, pVHL constitutively prevents HIF-1 to become active, but if the cell experiences hypoxia, pVHL fails to bind to the HIF-1α subunit and therefore an adequate stimulation of angiogenesis and erythropoiesis will establish an sufficient oxygen supply for the cells suffering hypoxia.
If pVHL cannot form, since VHL was deactivatied by (e.g.) mutation, HIF-1α is constitutively active, which leads to an inappropriate high level of these growth factors, which will favor tumor growth.